PROJECT SUMMARY/ABSTRACT Obesity and type 2 diabetes (T2D) are disorders of energy homeostasis. The brain is able to detect and utilize input from peripheral hormones and circulating nutrients to maintain metabolic homeostasis, and neurocircuits identified in the arcuate nucleus- median eminence (ARC-ME) of the mediobasal hypothalamus (MBH) are involved in the homeostatic defense of blood glucose and body fat mass. Consequently, disruption of these circuits may contribute to the pathogenesis of hyperglycemia in T2D. We previous reported that sustained diabetes remission can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) into rodent models of T2D. Our Preliminary Data show that bilateral intra-parenchymal microinjection of FGF1 targeting the ARC-ME in T2D Zucker Diabetic Fatty (ZDF) rats recapitulates the diabetes remission by icv FGF1. Transcriptomic analysis of the MBH after FGF1 implicates the upregulation of genes involved in extracellular matrix (ECM) reorganization and plasticity, and to explain the sustained anti-diabetic effect of FGF1, we hypothesize that FGF1 induces reorganization of ARC-ME neurocircuitry through remodeling of the surrounding ECM. Supporting this model is our recent finding that perineuronal nets (PNNs), a unique subtype of ECM that function to maintain neurocircuit synaptic integrity, are located selectively in the ARC-ME junction of rodents and humans and enmesh GABAergic/AgRP neurons involved in energy and glucose homeostasis, suggesting that the ECM in this brain area may play a role in maintaining neurocircuit stability and metabolic homeostasis. Here, we report that the stability of PNNs, indicated by chondroitin sulfate (CS) and CS-proteoglycan (CSPG) Aggrecan labeling, is significantly reduced in T2D-ZDF rats compared to normoglycemic WT controls. The integrity of ARC-ME PNNs tightly correlates to the ratio of 4S:6S-CS that constitute the PNN matrix, as increases in 6S-CS leads to decreased matrix integrity and destabilization of neural circuitry. Our Preliminary Data show the loss of ARC-ME PNNs in hyperglycemic rats associates with an increase in matrix destabilizing 6S-CS abundance. We propose to investigate whether hyperglycemia directly influences ARC-ME PNN abundance and composition, and whether these changes influence the responsiveness of ARC neurons to hormonal and nutrient stimuli. Remarkably, icv FGF1 stabilizes ARC-ME PNNs, indicated by the increase in stable matrix structures, in association with remission of diabetic hyperglycemia, and that this restoration correlates to a decrease in 6S-CS abundance. We propose to further characterize the mechanisms mediating these observed changes in PNN architecture and determine whether these changes are required for diabetes remission induced by FGF1. Overall, these results suggest that weakened PNN matrices within the ARC-ME may destabilize existing neural network interactions and promote the elevation blood glucose levels.